Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing of the amyloid precursor protein and Notch. We report here that nicastrin is most probably a type 1 transmembrane glycoprotein that is expressed at moderate levels in the brain and in cultured neurons. Immunofluorescence studies demonstrate that nicastrin is localized in the endoplasmic reticulum, Golgi, and a discrete population of vesicles. Glycosidase analyses reveal that endogenous nicastrin undergoes a conventional, trafficking-dependent maturation process. However, when highly expressed in transfected cells, there is a disproportionate accumulation of the endo--N-acetylglucosaminidase H-sensitive, immature form, with no significant increase in the levels of the fully mature species. Immunoprecipitation revealed that presenilin-1 interacts preferentially with mature nicastrin, suggesting that correct trafficking and co-localization of the presenilin complex components are essential for activity. These findings demonstrate that trafficking and post-translational modifications of nicastrin are tightly regulated processes that accompany the assembly of the active presenilin complexes that execute ␥-secretase cleavage. These results also underscore the caveat that simple overexpression of nicastrin in transfected cells may result in the accumulation of large amounts of the immature protein, which is apparently unable to assemble into the active complexes capable of processing amyloid precursor protein and Notch.
The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.
Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders.
Based on databases of Science Citation Index Expanded (1981-present) and Social Sciences Citation Index (2002-present), this paper applies the bibliometric method to analyze the scientific publications of low-carbon energy technology investment. By characterizing the basic information of the publications, we found: the historical development process is clearly divided into two stages; the field of low-carbon energy technology investment 1 has entered a stage of rapid development; the strength of developed countries is far greater than that of developing countries; the comprehensive strength of the United States ranks the first in the field, followed by UK and Denmark and only China and Turkey are developing countries among the top 15 countries; the auctorial collaboration degree in this field shows a clear upward trend, but institutional and national collaboration degrees are steady and relatively low. In addition, distributions of geography, journals and subjects, productive authors and institutions, frequently cited articles, etc. are obtained: articles in this area are mainly distributed in the USA, several countries in Europe and China; the most productive journal, author and institution are Energy Policy, Lund H from Denmark and National Technical University of Athens in Greece; Energy Fuel is the most popular subject among all the outcomes; the most frequently cited article is written by Demirbas published in Energy Policy in 2007. According to the frequency analysis of keywords, it reveals that: "renewable energy" is a kind of keyword used most frequently; "carbon capture and storage technology" is an emerging keyword which is increasingly concerned about; scholars pay widespread attention to electricity issues, especially the feed-in tariff; the policy mainly includes energy policy and climate policy; the real option theory is the most widely used theory; the existing uncertainty is summarized as the cost uncertainty and policy uncertainty. In the end, several suggestions for the future research are given.
Abstract:Missense substitutions in the presenilin 1 (PS1) and presenilin 2 (PS2) proteins are associated with earlyonset familial Alzheimer's disease. We have used yeasttwo-hybrid and coimmunoprecipitation methods to show that the large cytoplasmic loop domains of PS1 and PS2 interact specifically with three members of the armadillo protein family, including -catenin, p0071, and a novel neuronal-specific armadillo protein-neural plakophilinrelated armadillo protein (NPRAP). The PS1:NPRAP interaction occurs between the arm repeats of NPRAP and residues 372-399 at the C-terminal end of the large cytoplasmic loop of PS1. The latter residues contain a single arm-like domain and are highly conserved in the presenilins, suggesting that they form a functional armadillo protein binding site for the presenilins. Key Words: Presenilin proteins-Presenilin binding proteins-Armadillo proteins-Yeast-two-hybrid-Alzheimer's disease. J. Neurochem. 72, 999 -1008Neurochem. 72, 999 - (1999.The presenilin genes [presenilin 1 (PS1) and presenilin 2 (PS2)] encode homologous polytopic transmembrane proteins that are expressed at low levels in intracellular membranes, including the nuclear envelope, the endoplasmic reticulum, and the Golgi apparatus, and some as yet uncharacterized intracytoplasmic vesicles in many different cell types, including neuronal and nonneuronal cells (Levy-Lahad et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995;Doan et al., 1996;Walter et al., 1996;De Strooper et al., 1997;Lehmann et al., 1997;Li et al., 1997). Missense mutations in the PS1 and PS2 genes are associated with autosomal dominant forms of familial Alzheimer's disease (AD), an adult-onset degenerative disorder of the human CNS (Levy-Lahad et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995).Structural studies predict that the presenilins contain between six and eight transmembrane (TM) domains organized such that the N terminus, the C terminus, and a large hydrophilic loop following the sixth TM domain are located in the cytoplasm or nucleoplasm, whereas the hydrophilic loop between TM1 and TM2 is located within the lumen of membranous intracellular organelles (Doan et al., 1996;De Strooper et al., 1997;Lehmann et al., 1997). The physiological roles for the presenilins are unclear, although some evidence suggests roles in developmental signaling during embryonic differentiation (Levitan and Greenwald, 1995;Shen et al., 1997;Wong et al., 1997), in apoptotic signal transduction (Deng et al., 1996;Vito et al., 1996;Wolozin et al., 1996), and in the regulation of proteolytic cleavage of the -amyloid precursor protein (APP) (De Strooper et al., 1998). However, it is unclear how these putative physiological functions are mediated. It is also unclear how mutations in PS1 and PS2 alter the proteolytic cleavage of APP such that there is a relative increase in the production of longer -amyloid peptide (A) derivatives, i.e., an increase in the ratio of A42/A40 (Martins et al., 1995;Duff et al., 1996;Scheuner et al., 1996;Citron et al., ...
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